Semaglutide cardiovascular outcomes align more closely with attained dose than achieved weight loss.

Semaglutide is often optimized to maximize weight loss, yet it remains unclear whether long-term cardiovascular benefit is more closely associated with achieved weight reduction or therapeutic exposure. We conducted a retrospective observational study using a federated, de-identified U.S. electronic health record network comprising 47,199 patients with pre-existing cardiovascular disease who initiated semaglutide. Among 12,519 patients with at least two years of follow-up after initiation, dose escalation and weight change during the first two years (pre-landmark period) were evaluated in relation to cardiovascular outcomes during the subsequent two years (post-landmark period). Higher maximum semaglutide dose was strongly associated with greater weight loss during the pre-landmark period (3.15% additional weight loss per 1 mg increase; r = -0.97, P